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Biomedical subjects

G Montalescot

Publications and source records attributed to G Montalescot.

At least 73 records · Page 4Linked to original sources
PubMed1998

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Anticoagulants↗
PubMed1998

Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?

Whether the 677C-T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene acts as a risk factor for homocysteine-related vascular disease remains a matter of debate. Testing for the 677C-T nucleotide substitution and assay of plasma homocysteine were carried out simultaneously in 69 controls and 113 vascular disease patients from the Paris area. The variant gene frequency as well as the variant homozygous genotype frequency were very similar in controls and patients. Conversely, plasma homocysteine levels were substantially higher in patients than in controls. A slight interaction between the 677C-T MTHFR polymorphism and homocysteinaemia was observed in the patient group only, while a negative correlation between fasting homocysteine and plasma folate levels was found in all individuals homozygous for the 677C-T MTHFR genotype, irrespective of vascular disease. These data suggest that the 677C-T MTHFR polymorphism is not a major determinant of the vascular disease but contributes to increased plasma homocysteine concentration in conjunction with low plasma folate levels.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗
PubMed1998

Fibrinogen as a risk factor for coronary heart disease.

An elevated plasma fibrinogen level is associated with increased frequency of coronary heart disease and stoke. Although fibrinogen is also associated with other well-known risk factors such as smoking, age and diet, this paper discusses fibrinogen as an independent and modifiable risk factor for cardiovascular disease. There are several pathways by which acute or chronic increase in fibrinogen levels can lead to a cardiovascular event, especially and atherosclerotic event, including infiltration of the vessel wall by fibrinogen, rheological effects due to increase blood viscosity, increased platelet aggregation and thrombus formation, and increased fibrin formation. Elevated fibrinogen is a strong primary risk factor for cardiovascular disease in healthy individuals. It is also a risk factor for death or recurrence of myocardial ischaemia in patients with a previous coronary event, and a predictor of accelerated coronary atherosclerosis. Indeed, studies confirm that the positive association between plasma fibrinogen levels and cardiovascular events is a predictive as elevated cholesterol levels.

Cholesterol↗
PubMed1997

Indium-111 antimyosin scintigraphy before and after coronary bypass surgery: unexpected preoperative myocardial uptakes.

The present study was designed to evaluate 111In-antimyosin scintigraphy in detecting pre- and post-operative myocardial infarction in patients undergoing coronary artery bypass surgery. Fab antimyosin scintigraphy has been shown to be sensitive and specific in detecting myocardial necrosis and to be potentially valuable in situations where other criteria are not reliable. In a previous study, postoperative antimyosin uptakes occurred in 82% of the studied patients. Sixteen consecutive patients with an indication of coronary artery surgery were assessed by preoperative coronary angiography, serial electrocardiograms, and myocardial scanning with 111Indium-labeled antimyosin antibodies performed before and after operation. In four patients, a recent myocardial infarction (1 to 3 months) was detected with an accurate localization when compared to the classic criteria of myocardial infarction. One more patient with a 21-year old myocardial infarction showed an intense uptake whereas there was no recent acute coronary event. Four other patients had an unexpected preoperative uptake, since there were no acute coronary events in their medical history. All preoperative scintigraphic uptakes were still present on the second scan performed postoperatively in these nine patients. Only one patient showed a new postoperative uptake when compared to the preoperative scan which was normal; this postoperative septal infarct was confirmed by a postoperative coronary angiography. Extracardiac uptakes (sternum and ribs) were frequently observed after operation and might hamper the interpretation of postoperative scintigrams. Unexpected preoperative uptakes may be related to non diagnosed small necrosis. A preoperative reference scan is required for an accurate interpretation of a postoperative 111In-antimyosin uptake. Moreover, extracardiac uptakes may limit the interpretation of perioperative cardiac damage.

Aged↗
PubMed1997

Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease.

Homocysteine is a graded risk factor for the incidence of stroke and for the degree of carotid atherosclerosis. Homocysteine is also a graded risk factor for the incidence of myocardial infarction but we do not know its precise relations to the severity of atherosclerosis in coronary patients. Seventy five symptomatic coronary patients were recruited for the study. Fifty of these patients had coronary artery disease only and were compared in a case-control manner to 50 healthy controls matched for age and sex. The 25 other coronary patients had also symptoms in another atherosclerotic territory (cerebral, peripheral or both) and were also compared to 25 matched controls. Mean plasma homocysteine level was significantly higher in coronary patients than in controls (11.7 +/- 0.7 mumol l-1, n = 50 versus 9.9 +/- 0.5 mumol l-1, n = 50, p < 0.05). Homocysteine in patients with symptomatic atherosclerosis in two or three arterial sites was 15.7 +/- 1.5 mumol l-1 which differed significantly from matched controls and from patients with coronary artery disease only (p = 0.01). The extent of coronary atherosclerosis evaluated by an angiographic coronary score correlated weakly to plasma homocysteine levels (r = 0.25, p < 0.05). The patients with both hypertension and high levels of homocysteine (> 11.3 mumol l-1, median value) had more severe coronary atherosclerosis (coronary score of 16.3 +/- 2.3 versus 11.9 +/- 0.9, p < 0.05) and more diffuse atherosclerosis (number of atherosclerotic territories of 1.5 +/- 0.2 versus 1.2 +/- 0.7, p = 0.08) than the coronary patients without this association. There were no other high risk association when considering the other classical risk factors. Thus, the highest levels of homocysteine were present in patients with coronary disease and another symptomatic localisation of atherosclerosis. A small gradient in the extent of coronary atherosclerosis was found with increasing levels of homocysteine. The presence of both hypertension and hyperhomocysteinemia was associated with more severe coronary atherosclerosis.

Biomarkers↗
PubMed1997

[New antithrombotic agents in coronary disease].

Aspirin is effective in, treating patients with unstable angina or myocardial infarction. However, questions remain about the optimal dose of aspirin and aspirin-resistance in subgroups of patients. Heparin also has beneficial effects mostly during the acute phase of unstable angina, but thrombolytics are effective only in acute myocardial infarction and not in unstable angina. Recently, low molecular weight heparins have proved to be as effective (FRIC trial) or more effective (ESSENCE trial) than unfractionated heparin in unstable angina. Ongoing studies (TIMI 11B) are evaluating the efficacy of a prolonged administration of low molecular weight heparin to alter the chronic process of unstable angina. The new antiplatelet drugs directed against GP IIb/IIIa receptors are now available to improve the acute results of high risk percutaneous transluminal angioplasty (PTCA). This new drug (c7E3) binds rapidly to GP IIb/IIIa and prevents fibrinogen binding to the receptor. This very potent and irreversible effect prevents platelet aggregation and decreases the incidence of acute occlusions following PTCA. especially in patients with unstable angina. The counterpart is an increased risk of hemorrhage, knowing that patients receive simultaneously aspirin and heparin. The first results of the EPILOG study also demonstrate a better outcome in elective angioplasty without significant increase of serious bleeding, thanks to a low dose heparin regimen. In contrast to thrombolytics, the GP IIb/IIIa antagonist does not increase the risk of intracranial bleeding. The results of the CAPTURE trial also confirm the clinical benefit obtained with this drug in refractory unstable angina. The reduction of death and myocardial infarction is very consistent throughout the studies performed with c7E3. The Kaplan-Meier curves of freedom of death and myocardial infarction diverge immediately after start of study medication. The acute benefits are preserved at 3 years in the EPIC trial. Similar trends were present during the acute phase with other compounds (tirofiban, integrelin), meaning that a class effect may exist but the long term results are disappointing. The results with new direct antithrombins such as hirudin, or hirulog in acute myocardial infarction or in PTCA for unstable angina are negative. The development of new potent oral antiplatelet drugs might change the treatment of acute coronary syndromes in the future. The current progress made with antithrombotic drugs should improve the prognosis of acute coronary syndromes.

Anticoagulants↗
PubMed1997

[Use of abciximab during coronary angioplasty].

The IIb-IIIa glycoprotein is the platelet receptor of fibrinogen and the final common pathway of platelet activation and aggregation. Abciximab is a Fab fragment of the chimeric monoclonal antibody (c7E3) interfering with the glycoprotein receptor. It is the only anti IIb-IIIa currently available, commercialized under the name of Reopro. Preliminary clinical data has been obtained with its use in high risk coronary angioplasty. The EPIC trial showed a 35% relative reduction of the principal combined criterion of judgement of cardiac morbidity and mortality at 1 month, a benefit even greater in acute coronary syndromes (-72%) than in programmed procedures for complex type C lesions (-10%). The incidence of severe bleeding was high (14%). The results of the CAPTURE trial could widen the indications of abciximab to include the period surrounding angioplasty for unstable angina as the use of Reopro in the 24 hours before the procedure significantly reduced the risk of ischaemic events (10.8% versus 16.4%). In programmed angioplasty, the EPILOG trial investigated the effects of adapting the dose of heparin and an infusion of abciximab to body weight early (4th to 6th hour) withdrawal of the arterial introducer without continuing heparin. Using a 70 IU/Kg dosage modulated to algorithms taking into account the ACT, the incidence of bleeding complications was reduced to 1.8%, the same as the control group, and the benefits with regards to ischaemic events were not only maintained but increased (a 56% reduction at 1 months). Utilization of abciximab would be supported by the Cost saving approach of the EPIC trial 3-years follow-up which showed presentation of the initial benefits.

Abciximab↗
PubMed1996

[Hyperhomocysteinemia in coronary artery diseases. Apropos of a study on 102 patients].

Homocystein is at the crossroads of the metabolic pathways of sulphuric amino acids. Homocystinuria is a congenital autosomal recessive disease, usually related to cystathionine beta-synthetase deficiency. Children with homozygotic forms of the disease have early vascular complications which represent the main cause of death. Moderately elevated serum homocystein levels are related to two major genetic factors (heterozygotic cystathionine beta-synthetase deficiency and mutation of the 5-10 methylene tetrahydrofolate reductase) and several minor, genetic and non-genetic factors (folic acid, vitamins B6 and B12 and betain deficiencies). Previous studies have suggested that hyperhomocysteinaemia could be a cardiovascular risk factor. This study was based on 222 subjects including 102 consecutive patients with angiographically documented coronary artery disease and 120 control subjects without vascular disease. No relationship was observed between serum homocystein concentrations and the classical cardiovascular risk factors. Coronary patients had higher average homocystein concentrations than control subjects (11.27 +/- 0.52 vs 8.77 +/- 0.31 mumol/l); p < 0.0001): moreover, the prevalence of hyperhomocysteinaemia (> 15.67 mumol/l) was higher in the coronary group (15.7%) than in the controls (2.5%). A significant relationship was also observed between homocystein concentrations and the severity of the coronary disease (defined by a coronary score) and the number of diseased vascular territories. These results underline the relationship between homocystein and vascular risk, especially that of coronary artery disease. The treatment of hyperhomocysteinaemia by folic acid supplements is effective in correcting plasma levels, without side effects and at a relatively low cost.

Adult↗
PubMed1995

Fibrinogen after coronary angioplasty as a risk factor for restenosis.

BACKGROUND: Fibrinogen is a risk factor for cardiovascular disease and is related to the severity of coronary atherosclerosis. Its role in restenosis after coronary angioplasty remains unknown. Although platelets and thrombosis contribute to the pathogenesis of restenosis, few clinical data are available concerning the relations between restenosis and proteins of the coagulation and fibrinolytic systems. METHODS AND RESULTS: In 107 consecutive patients undergoing coronary angioplasty, we measured plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor, and fibrinogen before and immediately after angioplasty and at a 6-month follow-up. The individual changes of intraluminal diameter were measured by quantitative coronary angiography, and patients were classified according to four definitions of restenosis: (1) a final stenosis > 50%, (2) a loss of minimal luminal diameter during the follow-up period greater than the measurement variability in our laboratory (> 0.52 mm), (3) a loss of at least 50% of the gain in luminal diameter achieved by angioplasty, and (4) the combination of definitions 1 and 2. The relations between coagulation variables and each definition of restenosis were assessed univariately; then with the clinical variables included, the relations were analyzed multivariately. Angiographic follow-up was obtained in 92% of patients with a primary success of angioplasty. Global restenosis rates were 38%, 43%, 48%, and 30% for definitions 1 through 4, respectively. Plasma levels of t-PA antigen and PAI-1 antigen were not associated with any of the four definitions of restenosis. Multivariate analysis demonstrated that von Willebrand factor measured immediately after angioplasty predicted restenosis according to definitions 2 and 3. Fibrinogen measured within 6 months of follow-up was significantly increased in all restenosis groups of the four definitions. Patients with a fibrinogen concentration > 3.5 g/L at follow-up had higher restenosis rates than patients with a concentration < 3.5 g/L: 55% versus 22% (P = .001), 68% versus 31% (P = .002), 63% versus 37% (P = .01), and 74% versus 26% (P = .002) for definitions 1 through 4, respectively. The loss index was lower (P = .003) and the net gain higher (P = .03) in patients with a fibrinogen level < 3.5 g/L. There was a significant correlation between fibrinogen level and angiographic loss index (r = .41; P < .0001). Multivariate analysis confirmed that the fibrinogen level predicted restenosis with all definitions. CONCLUSIONS: An independent relation exists between von Willebrand factor measured immediately after angioplasty and restenosis defined by the degree of intraluminal renarrowing. An elevated fibrinogen level during follow-up is a strong biochemical predictor of restenosis. Therefore, fibrinogen should be considered at least as an independent marker of restenosis and perhaps as a common risk factor for both spontaneous coronary atherosclerosis and postangioplasty restenosis, which is an accelerated form of atherosclerosis.

Angioplasty, Balloon, Coronary↗
PubMed1995

[Use of aspirin in coronary disease].

The beneficial effect of aspirin in different situations of coronary artery disease has been clearly demonstrated, but prescription remains empirical due to the lack of phase II trials and the incompletely understood mechanism of action. Since the ISIS-2 study was published in 1988, aspirin is indicated in the acute phase of myocardial infarction as mortality can be reduced by 20% and the rate of reocclusions reduced. The beneficial effect of aspirin in unstable angina has also been demonstrated with a reduction of more than 50% in the combined incidence of mortality and myocardial infarction. Stable angina is an ideal application for low-dose aspirin with an improvement in combined incidence of myocardial infarction and sudden death of 34%. The question of dose remains open. When prescribed for primary or secondary prevention, aspirin should be given at low-doses (50-100 mg/d) in a long-term regimen. The dose should be examined differently for treatment of acute thrombotic events including infarction and unstable angina. Doses above 250 mg/d with an initial dose of 500 mg to 1 g are recommended followed by a relay with 50 to 100 mg/d. Irreversible dose-dependent inhibition of platelet cyclooxygenase by aspirin is nearly total for a single dose of 100 mg. The effect is cumulative for smaller doses and since the anucleated platelets cannot resynthesize the enzyme only new platelet can recover enzymatic activity. The duration of the effect thus is a function of normal platelet turn-over (8 days). Currently, aspirin is indicated in all coronary artery patients and should be discussed for "potential" patients i.e. as primary prevention in healthy subjects at risk of coronary artery disease although the threshold of risk requiring prescription remains to be clearly determined.

Angina Pectoris↗
PubMed1995

[Coronary restenosis: the cardiologist facing problems of definitions].

Many angiographic definitions have been proposed to define restenosis after coronary angioplasty. The utility of each remains poorly defined. The aims of this study were: a) to analyse groups of patients defined by each of three criteria: > 50% stenosis (definition 1), loss > or = 50% of initial gain in diameter (definition 2), loss > or = 0.52 mm of minimal luminal diameter based on the variability of the angiographic measurement (definition 3) and, b) to compare the immediate attitude of the interventional cardiologist with the deferred quantitative angiographic analysis. The angiographic follow-up included 89 patients. The angiographic restenosis rate was 37% (definition 1), 48% (definition 2) and 43% (definition 3). Restenosis as defined by criterion 1 was associated with the greatest degree of postangioplasty residual stenosis (p = 0.02) whereas, with criteria 2 and 3, it was associated with less severe residual stenosis (p = 0.03 and p = 0.007). Definition 2 and 3 are the most similar and definitions 1 and 3 the most complementary. The sensitivity, specificity positive and negative predictive values for recurrence of angina with respect to angiographic restenosis (definition 1) were respectively 63.6%, 77.8%, 63.6%, and 77.8% and are not significantly improved by associated analysis of exercise testing. Discordances between the decision of the interventional cardiologist and the results of quantitative angiography (definition 1) were noted in 12.4% of the stenosis studied, there measuring 44 to 64%. The judgement of the cathetiser of these intermediary stenoses was essentially influenced by the recurrence of angina during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1995

[What dose of aspirin should be prescribed in patients with coronary disease?].

Aspirin is prescribed in almost all coronary patients. However, the prescription modalities tend to vary, partly because of the absence of phase II development of this molecule as an antithrombotic agent in coronary patients. The dose of 162.5 mg has been shown to be effective during the acute phase of myocardial infarction, but we do not know whether this is the most effective dose. A higher dose, in particular 500 mg to 1 g, would have the advantage of more rapidly and more completely blocking platelets during an acute thrombotic phase. After this first high dose, lower doses, less than 100 mg, could be administered in the long term. These low doses of aspirin, generally 75 mg, have been demonstrated, in stable angina, to decrease infarction and sudden death by more than 30%. This dose has also been demonstrated to be effective in the long-term in unstable angina, but once again this low dose should be introduced after an initial higher dose for this acute coronary syndrome. A primary prevention study is currently underway using the dose of 75 mg per day following the trial in American physicians using a dose of 320 mg every second day. Long-term low doses have a clearly demonstrated efficacy in chronic prevention and have the advantage of inducing much fewer adverse effects, particularly gastrointestinal haemorrhage. In conclusion, a high initial dose should be recommended in acute coronary syndromes and a low dose, less than 100 mg, should be recommended for chronic prevention. Buffered forms, protecting the stomach, and sustained-release forms are impatiently awaited to further improve the benefit/risk ratio of aspirin, which is nevertheless already excellent.

Aspirin↗
PubMed1995

[Indium III monoclonal antimyosin antibody scintigraphy for the detection of chronic myocardial infarction apart from the acute phase].

Fab antimyosin scintigraphy has been shown to be sensitive and specific in detecting acute myocardial necrosis. This study was designed to evaluate the preoperative frequency of Indium-111 (In-111) antimyosin myocardial uptake in patients scheduled for coronary artery bypass surgery. The scintigraphic results were compared with other criteria of myocardial infarction (MI). Sixteen consecutive patients were included. Recent MI (1 to 3 months) were detected in four patients, with an accurate localization in three cases when compared to the classic criteria for MI. Two more patients had old Q wave MI: one did not show any uptake in the territory of MI whereas the second patient with a 21 year old infarct without recent acute coronary events showed an intense uptake consistent with the ECG and angiographic localization. Four other patients with stable angina showed limited uptakes that were unexpected, since there were no acute coronary events in their medical history, and ECG. Their left ventricle angiography were considered as normal. In these four cases, the scintigraphic location corresponded to a territory supplied by an occluded coronary artery (n = 2) or by a coronary artery with a tight stenosis requiring a bypass graft (n = 2). These antimyosin uptakes are probably related to small necroses which did not modify the ECG and did not alter the ventricular segmental wall motion. We conclude: 1) recent MI are detected by In-111 antimyosin scintigraphy; 2) In-111 antimyosin uptake may occur in patients without a diagnosis of recent myocardial infarction and correspond to older MI or limited necroses without detectable changes of the ECG and left ventricle angiography.

Aged↗
PubMed1994

Endothelin-1 in patients with coronary heart disease undergoing cardiac catheterization.

OBJECTIVES: This study examined the possible association between endothelin and coronary atherosclerosis and evaluated the synthesis and release of endothelin in the presence of various stimuli that occur during cardiac catheterization. BACKGROUND: Circulating endothelin has been reported to be increased in diffuse atherosclerosis and acute myocardial infarction. However, the relation between coronary artery disease and endothelin release remains unclear. METHODS: We measured the plasma and urinary concentrations of endothelin immunoreactivity in 45 patients and 10 healthy control subjects. RESULTS: In group IA (n = 9), simultaneous blood sampling in the coronary sinus and femoral artery during coronary angioplasty of the left anterior descending coronary artery demonstrated no immediate changes in plasma immunoreactive endothelin-1 (ir-ET-1) levels. In 11 patients in group IB undergoing coronary angioplasty of a major artery, we did not detect changes in peripheral plasma concentrations of ir-ET-1 within 24 h, but urinary ir-ET-1 levels increased from 9.2 +/- 2.3 to 18.6 +/- 4.9 pg/mg of creatinine a few hours after coronary angioplasty (mean +/- SEM, p < 0.05). This increase in urinary endothelin excretion persisted 24 h later. Group II patients (n = 12) had coronary angiography without coronary angioplasty. Levels of both plasma and urinary ir-ET-1 did not change during the 24-h follow-up period. There was no relation between the severity of coronary atherosclerosis and the plasma or urinary concentrations of ir-ET-1. Systolic aortic pressure correlated with basal urinary excretion of endothelin (r = 0.54, p = 0.03, n = 15). In group III (n = 13), levels of ir-ET-1 in patients undergoing right heart catheterization without angiography did not differ from those in the control group. CONCLUSIONS: The presence or the severity, or both, of coronary atherosclerosis is not associated with a detectable increase in endothelin release. The diagnostic procedures of catheterization do not modify endothelin concentrations in plasma and urine. Vascular stretch or injury, or both, during coronary angioplasty increases urinary ir-ET-1 levels a few hours after the procedure. This increase persists for at least 24 h but is not detectable by brief sampling of peripheral or coronary sinus blood.

Angioplasty, Balloon, Coronary↗